The goal of this project is to use magnetic resonance imaging (MRI) to examine the natural history and potential therapeutic approaches in multiple sclerosis (MS). Emphasis has been placed on investigation of the early MS lesion which is characterized by enhancement on T1 weighted MRI images following administration of gadolinium-DTPA (Gd). Results from initial studies have indicated that MS can be an active disease, even during periods of remission in the early relapsing-remitting phase of the illness. The correlation between the frequency or area of Gd-enhancing lesions and episodes of clinical worsening has been examined. Although most Gd-enhancing lesions occurring in the cerebrum are clinically silent, episodes of worsening tend to occur during periods of increased disease activity as evidenced by increased frequency or area of enhancing lesions. The clinical symptoms and signs generally are due to lesions occurring in the spinal cord or brain stem concurrently with the increased activity in the cerebrum. These results demonstrate a correlation between clinical worsening and periods of increased disease activity occurring in the cerebrum and indicate that the regulation of disease activity as measured by Gd enhancement seems similar in the cerebrum and spinal cord. Examination of the pathological changes occurring in conjunction with Gd enhancement indicate an acute inflammatory process with prominent perivascular cuffs of lymphocytes. These findings support the hypothesis that Gd enhancement represent the initial step in lesion development. Treatment trials using MRI as the primary outcome measure are now underway and indicate that the response to therapy is heterogeneous further complicating assessment of the results of clinical trials. This later finding strengthens the need for an objective measure of disease activity, such as MRI, to assess results of therapeutic trials.